The present invention is concerned with a process for the preparation of vinyl pyrimidine derivatives. More particularly, the present invention is concerned with a process for vinylating pyrimidine derivatives, such as cytosine and cytidine derivatives.
5xe2x80x2-Deoxy-5-vinylcytidine derivatives are of interest in the therapy of cancer, see International application PCT/EP99/00710. However, the preparation of these compounds as disclosed in said International application does not proceed in satisfactory yield and involves the use of tri-n-butyl vinyl stannane, a costly and toxic reagent which also gives rise to tedious purification of the final product and problems in disposing of toxic waste.
In accordance with the present invention it has been found that the vinylation of pyrimidine derivatives can be accomplished with the use of vinyl boranes. The process in accordance with the present invention proceeds in superior yield and does not provide the economic and environmental problems of the prior art process.
In one aspect, the present invention is concerned with a process for the preparation of compounds of the formula I 
wherein R1 is hydrogen or a carboxylic ester group, and R2 is hydrogen or a group of the formula (a) 
wherein Ra is hydrogen, a hydroxy protecting group or a group easily hydrolyzable under physiological conditions, which comprises reacting a compound of the formula II 
wherein R21 is hydrogen or a group (a) wherein hydroxy groups are optionally protected, R3 is bromo, chloro or iodo, and R1 is as above, with a vinyl borane compound of the formula IIIa or IIIb
(CH2xe2x95x90CH)nB(R6)3xe2x88x92nLmxe2x80x83xe2x80x83(IIIa)
[(CH2xe2x95x90CH)pB(R6)4xe2x88x92p]X+xe2x80x83xe2x80x83(IIIb)
wherein
n is 1, 2 or 3;
m is 0 or 1;
R6 is hydrogen, halogen, alkyl, cycloalkyl, alkoxy, cycloalkoxy, hydroxy or aryl, and wherein, if more than one group R6 is present, these groups may be different from each other, or two groups R6 may, together withxe2x80x94Axe2x80x94(CH2)qxe2x80x94Yxe2x80x94(CH2)rxe2x80x94Axe2x80x94, form a carbocyclic or heterocyclic ring wherein A and Y are CH2 or NH or O and q and r are an integer from 0-4, or two groups R6 may also form a catechol moiety 
xe2x80x83in which R is hydrogen or lower alkyl;
L is an amine, a Schiff base or an ether;
p is 1, 2, 3 or 4;
X+ is a cation;
in the presence of a Pd complex and a base, and, if desired, removing any protecting group from a compound of formula I wherein R2 is a group (a).
The compounds of formula I are known (for example, see U.S. patent application Ser. No. 09/484,174, filed Jan. 14, 2000 and U.S. Pat. No. 6,005,098, both herein incorporated by reference).
As used herein the term xe2x80x9ccarboxylic ester groupxe2x80x9d preferably denotes a group xe2x80x94COOR4 wherein R4 is xe2x80x94(CH2)n-cycloalkyl [wherein cycloalkyl consists of 3 to 6 carbon atoms, n is an integer from 0 to 4], heteroaryl-(lower-alkyl), (lower-alkoxy)-(lower-alkyl), aryloxy-(lower-alkyl), aralkyloxy-(lower-alkyl), (lower-alkylthio)-(lower-alkyl), arylthio-(lower-alkyl), aralkylthio-(lower-alkyl), oxo-(lower-alkyl), acylamino-(lower-alkyl), cyclic amino-(lower-alkyl), (2-oxocyclic amino)-(lower-alkyl) wherein the alkylene chain may be further substituted with one or two lower-alkyl group(s). The term xe2x80x9clowerxe2x80x9d means groups containing up to and including 5 carbon atoms. xe2x80x9cAcylxe2x80x9d denotes aliphatic or aromatic carboxylic moieties such as lower alkanoyl or benzoyl.
Examples of the group xe2x80x94(CH2)n-cycloalkyl are cyclobutyl, cyclopropylmethyl and cyclopentylmethyl. Examples of heteroaryl-(lower-alkyl) are pyridin-3-ylmethyl, pyridin-2-ylmethyl, pyridin-4-ylmethyl, 1-(pyridin-4-yl)ethyl, (6-methylpyridin-2-yl)methyl and 1-(6-ethylpyridin-2-yl)propyl. Examples of (lower-alkoxy)-(lower-alkyl) are 2-methoxy-ethyl, 2-thoxyethyl, 3-methoxypropyl, 3-ethoxypropyl, 3-methoxy-3-methylbutyl, 3-ethoxy-3-methylbutyl, 3-methoxy-2,2-dimethylpropyl, 3-ethoxy-2,2-dimethylpropyl, 2-ethyl-2-methoxymethylbutyl and 2-ethyl-2-ethoxymethylbutyl. Examples of aryloxy-(lower-alkyl) are 2-phenoxyethyl, 1-phenoxypropyl and 3-phenoxypropyl. Examples of aralkyloxy-(lower -alkyl)are 2-benzyloxyethyl, 3-benzyloxypropyl and 5-benzyloxypentyl. Examples of (lower-alkylthio)-(lower-alkyl) are 2-methylthioethyl, 2-ethylthioethyl, 3-methylthiopropyl and 3-ethylthiopropyl. Examples of arylthio-(lower-alkyl) are 2-phenylthioethyl and 3-phenylthiopropyl. Examples of aralkylthio-(lower-alkyl) are 2-(benzylthio)ethyl and 3-(benzylthio)propyl. Examples of oxo-(lower-alkyl) are 4-oxopentyl, 3-oxo-2-methylbutyl and 2-oxobutyl. Examples of acylamino-(lower-alkyl) are 2-(acetylamino)-ethoxy, 3-(acetylamino)propyl, 3-(n-propionylamino)propyl and 3-(benzoylamino)propyl. Examples of cyclic amino-(lower-alkyl) are 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-pyrrolidinoethyl and 3-pyrrolidinopropyl. Examples of (2-oxocyclic amino)-(lower-alkyl) are 2-oxopyrrolidin-1-ylethyl and 2-oxopiperidin-1-ylethyl. Preferably, R1 is hydrogen.
The term xe2x80x9ca group easily hydrolyzable under physiological conditionsxe2x80x9d preferably means acetyl, propionyl, benzoyl, toluoyl, glycyl, alanyl, xcex2-alanyl, valyl or lysyl. Examples of hydroxy protecting groups are acetyl, benzoyl, trimethylsilyl and tert.butyldimethylsilyl. Preferably, Ra is acetyl which serves as physiologically hydrolyzable and protecting group as well.
Preferred vinyl boranes of formula IIIa and IIIb are those of the formulae 
The preferred vinyl boranes are potassium vinyl trifluoroborate and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolan.
The Pd complex used as a catalyst in the vinylation reaction according to the invention can be a neutral Pd(0) or Pd(II) complex or a cationic Pd(II) complex. Examples of such Pd complexes are Pd(OAc)2, Pd(OAc)2/dppf, Pd(OAc)2/dppp, Pddba2, Pd2dba3, Pd2dba3/PPh3, Pd2dba3/P(O.Tol)3, Pd2dba3/P(mTol)3, Pd2dba3/P(2-Furyl)3, PdCl2dppf, PdCl2(PPh3)2, PdCl2dppe, PdCl2(NCMe)2, PdCl2(NCMe)2/(R)-BIPHEMP, Pd2Cl2(xcfx80-allyl)2, Pd(PPh3)4, [Pd(NCMe)4](BF4)2, Pd/C, and Bedford""s catalyst, wherein the structures of the phosphines present in the above recited catalysts are as shown below: 
As used above, the term xe2x80x9cPhxe2x80x9d means phenyl and xe2x80x9cdbaxe2x80x9d means dibenzylideneacetone.
The preferred catalysts for the vinylation reaction are PdCl2(dppf) and Pd2dba3/PPh3. All the Pd catalysts are known from literature and are commercially available, e.g. from Fluka, Buchs S G, Switzerland, or Strem Chemicals, Kehl, Germany, or can be prepared in situ from commercially available components. The synthesis of (R)-BIPHEMP is described in EP 104 375.
Suitably, the vinylation reaction according to the invention is carried out in the presence of a base. The base can be an organic base such as a tertiary, secondary and primary amine, e.g. triethyl amine, diisopropyl ethylamine, tert-butyl amine, pyrrolidine, pyridine, alkali alcoholates such as potassium ethylate, or a salt of a carboxylic acid such as sodium acetate; or an inorganic base e.g., a carbonate such as sodium carbonate and potassium hydrogen carbonate, or hydroxide, or salt of phosphoric acid, sulfuric acid and fluoric acid such as K3PO4 and CsF2. Preferred bases are triethyl amine and tributyl amine.
Suitably, the vinylation is carried out in the presence of a solvent such as water, lower aliphatic alcohols, e.g. methanol, ethanol, n-propanol, iso-propanol or n-butanol, nitrites, e.g. acetonitrile, hydrocarbons such as toluene, halogenated hydrocarbons, e.g. methylene chloride, esters, e.g., ethyl acetate, amides, e.g. dimethylformamide, pyridine or N-methyl pyridine, ethers, e.g. tetrahydrofuran or dioxan, urethanes, e.g. TMU, sulfoxides, e.g. DMSO or mixtures thereof. The preferred solvent for the vinylation reaction is ethanol or methanol.
The reaction temperature is not critical and can be, e.g., within the range of 0-200xc2x0 C., preferably 40-150xc2x0 C. The amount of catalyst is not narrowly critical. For example, 1-10 000 moles, preferably 10-200 moles of substrate can be used per mol of catalyst. The amount of vinyl borane is preferably 1-10 equivalents; and the amount of base is preferably 0-10 equivalents, more preferably 0-1.5 equivalents.
The compounds of formula II are known (for example, see U.S. patent application Ser. No. 09/484,174, filed Jan. 14, 2000 and U.S. Pat. No. 6,005,098), or can be prepared by conventional methods from known starting materials. The compounds of formulas IIIa and IIIb are known (for example, see Darses et al., Tetrahedron Letters 39 (1998) 5045-5048, incorporated herein by reference), or can be prepared by conventional methods from known starting materials.
In a preferred aspect, the invention is concerned with the vinylation of a compound of formula II wherein R1 is hydrogen and R2 is a group (a) as defined above. According to this preferred aspect, the reaction is most suitably carried out using a compound of formula II wherein R3 is bromo and the vinyl borane compound is potassium vinyltrifluoroborate. Furthermore, the reaction according to this preferred aspect is most suitably carried out using PdCl2(dppf) as the catalyst.
In another aspect, the invention is concerned with the vinylation of a compound of formula II wherein R1 is hydrogen and R2 is hydrogen. According to this aspect, the reaction is most suitably carried out using a compound of formula II wherein R3 is iodo and the vinyl borane compound is 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolan. Furthermore, the reaction according to this preferred aspect is most suitably carried out using Pd2dba3/PPh3 as the catalyst.
In another aspect of the invention, the invention is concerned with the further conversion of a compound of formula I wherein R2 is hydrogen by reaction with a compound the formula IV 
wherein Rb is a hydroxy protecting group and Z is a leaving group, in the presence of a Lewis acid catalyst to yield a compound of formula I wherein R2 is a group (a), whereupon, if desired, a hydroxy protecting group Rb is removed. The leaving group can be any leaving group that""s is customary in such coupling reactions, for example, an acyl group such as acetyl or benzoyl or halogen, such as chloro. Preferably, the leaving group is acetyl. Specific examples of the compound represented by the general formula (IV) include the known 5-deoxy-1,2,3-tri-O-acetyl-D-ribofuranoside, 5-deoxy-1,2,3-tri-O-benzoyl-D-ribofuranoside, and the like.
Examples of Lewis acids for use in this reaction are tin(IV) chloride, titanium(IV) chloride, trifluoromethane sulfonic acid and the like. This coupling reaction can be carried out in a solvent such as acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, nitromethane, toluene and the like, at a temperature between 0 and 50xc2x0 C.
In the reaction product of the formula I a hydroxy protecting group can be removed in a manner known per se, such as base hydrolysis.
The invention is illustrated further by the Examples which follow.
A. Preparation of the Starting Compounds